Expression in Yeast Links Field Polymorphisms in PfATP6 to in Vitro Artemisinin Resistance and Identifies New Inhibitor Classes

Pulcini, Serena; Staines, Henry M.; Pittman, Jon K.; Slavic, Ksenija; Doerig, Christian; Halbert, Jean; Tewari, Rita; Shah, Falgun; Avery, Mitchell A.; Haynes, Richard K.; Krishna, Sanjeev

doi:10.1093/infdis/jit171

Cited by 27 publications

(50 citation statements)

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“…In addition to the four MDRs (MDR1, MDR4, MDR6, and MDR7) 22, these include the putative cation transporting ATPase, ATP4, (S. Kenthirapalan, K. Matuschewski, T.W.A. Kooij, unpublished data), ATP6 45 and the V-type proton ATPase subunit G 46, ABCI3, and four predicted aminophospholipid transporters 23.…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Weiner

Kooij

2016

Microb Cell

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In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

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Section: Resultsmentioning

confidence: 99%

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Weiner

Kooij

2016

Microb Cell

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“…Artemisinin derivatives also exhibit activities against several other parasites, such as Schistosoma (12) and Babesia (13), and against cancer cells (14,15). Artemisinin may exert its antimalarial effect by perturbing the cellular redox cycling or the sarco(endo)plasmic reticulum Ca 2ϩ ATPase (SERCA) pump (16). However, the precise mechanism of action of these drugs against malaria, Schistosoma, and cancer cells remains unknown.…”

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confidence: 99%

Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway

Deng

Wei

Man

et al. 2015

Antimicrob Agents Chemother

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dAcanthamoeba sp. parasites are the causative agents of Acanthamoeba keratitis, fatal granulomatous amoebic encephalitis, and cutaneous infections. However, there are currently no effective drugs for these organisms. Here, we evaluated the activity of the antimalarial agent artemether against Acanthamoeba castellanii trophozoites and identified potential targets of this agent through a proteomic approach. Artemether exhibited in vitro amoebicidal activity in a time-and dose-dependent manner and induced ultrastructural modification and cell apoptosis. The iTRAQ quantitative proteomic analysis identified 707 proteins that were differentially expressed after artemether treatment. We focused on phosphoglycerate dehydrogenase and phosphoserine aminotransferase in the serine biosynthesis pathway because of their importance to the growth and proliferation of protozoan and cancer cells. The expression of these proteins in Acanthamoeba was validated using quantitative real-time PCR and Western blotting after artemether treatment. The changes in the expression levels of phosphoserine aminotransferase were consistent with those of phosphoglycerate dehydrogenase. Therefore, the downregulation of phosphoserine aminotransferase may be due to the downregulation of phosphoglycerate dehydrogenase. Furthermore, exogenous serine might antagonize the activity of artemether against Acanthamoeba trophozoites. These results indicate that the serine biosynthesis pathway is important to amoeba survival and that targeting these enzymes would improve the treatment of Acanthamoeba infections. Artemether may be used as a phosphoglycerate dehydrogenase inhibitor to control or block Acanthamoeba infections.

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“…When PfATP6 homologues PMR1 and PMC1 were removed, the mutant yeast grew slightly more slowly but displayed insensitivity against ART 72. When PfATP6 was introduced to the mutant and expressed, ART acted to partially block the calcium-altering effect which PfATP6 conferred on the yeast 73. These experiments would suggest that ART targets PfATP6.…”

Section: Yeast Research Related To Other Models Of Art’s Actionmentioning

confidence: 98%

The molecular and cellular action properties of artemisinins: what has yeast told us?

Sun¹,

Zhou²

2016

MIC

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Artemisinin (ART) or Qinghaosu is a natural compound possessing superior anti-malarial activity. Although intensive studies have been done in the medicinal chemistry field to understand the structure-effect relationship, the biological actions of artemisinin are poorly understood and controversial. Due to the current lack of a genetic amiable model to address this question, and an accidental finding made more than a decade ago during our initial exploratory efforts that yeast Saccharomyces cerevisiae can be inhibited by artemisinin, we have since been using the baker’s yeast as a model to probe the molecular and cellular properties of artemisinin and its derivatives (ARTs) in living cells. ARTs were found to possess potent and specific anti-mitochondrial properties and, to a lesser extent, the ability to generate a relatively general oxidative damage. The anti-mitochondrial effects of artemisinin were later confirmed with purified mitochondria from malaria parasites. Inside some cells heme appears to be a primary reducing agent and reduction of ARTs by heme can induce a relatively nonspecific cellular damage. The molecular basis of the anti-mitochondrial properties of ARTs remains not well elucidated yet. We propose that the anti-mitochondrial and heme-mediated ROS-generating properties constitute two cellcidal actions of ARTs. This review summarizes what we have learned from yeast about the basic biological properties of ARTs, as well as some key unanswered questions. We believe yeast could serve as a window through which to peek at some of the biological action secrets of ARTs that might be difficult for us to learn otherwise.

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Expression in Yeast Links Field Polymorphisms in PfATP6 to in Vitro Artemisinin Resistance and Identifies New Inhibitor Classes

Abstract: The identification of inhibitors effective against mutated PfATP6 suggests ways in which artemisinin resistance may be overcome.

Cited by 27 publications

References 50 publications

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Artemether Exhibits Amoebicidal Activity against Acanthamoeba castellanii through Inhibition of the Serine Biosynthesis Pathway

The molecular and cellular action properties of artemisinins: what has yeast told us?

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